DESCRIPTION (Applicant's abstract): The hippocampus is necessary for some (e.g., episodic), but not all forms of learning and memory. The same mechanisms that underlie synaptic plasticity in the hippocampus may also be required for learning and memory tasks that require the structure. Thus, both learning and the induction of long-term potentiation (LTP) require the same mechanisms, including the activation of protein kinases. The persistence of learning and LTP both require de novo protein synthesis, and several immediate and delayed early genes have been identified that may be crucial for both learning that depends upon hippocampal function and for LTP. Together, the evidence suggests strongly that the persistence of hippocampus dependent learning requires a biochemical cascade that includes de novo protein synthesis in hippocampal neurons. The development of microarray technologies provides, for the first time, a method for determining the precise temporal sequence of gene expression in the hippocampus that underlies this crucial type of memory. Aim 1: To identify the temporal sequence of gene activation in the hippocampus after rats learn a task that requires the hippocampus by using microarray technologies. We hypothesize that successful learning and memory require a selective, temporally extended sequence of genes to be expressed in the hippocampus that is distinct from that activated by behavior or neural activity per se. We will test rats trained in a water maze task that can be solved by either hippocampus-dependent or independent strategies. Probe tests will be used to assess the strategies used by each rat, and gene activation will be compared in normal spatial and cue learners, fornix lesioned rats who learn only cue-response strategies and rats matched for swimming stress. Gene profiles will be assessed 15 min, 2 h, and 12 h after training to determine the temporal sequence of expression. Aim 2: To distinguish learning related expression changes from those related simply to behavior or lesion effects, a second experiment will train rats in the same task as above, but will test the effects of NMDA receptor antagonists that block long-term potentiation (LTP), spatial learning, and the stabilization of hippocampal place fields. We hypothesize that the specific, temporally extended sequence of gene expression in the hippocampus that is required for hippocampus-dependent learning is initiated by the same intracellular signaling pathway that is required for LTP. The use of this pharmacological "plasticity clamp" will enable us to distinguish genes that are expressed due to specific patterns of neuronal activity from those that are needed for plasticity per se.